CSP

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One-pot synthesis of aminoindolizines and chalcones using CuI/CSP nanocomposites with anomalous selectivity under green conditions Chinna Rajesh U., Gunjan Purohit, and Diwan S. Rawat ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.5b00701 • Publication Date (Web): 04 Sep 2015 Downloaded from http://pubs.acs.org on September 5, 2015

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ACS Sustainable Chemistry & Engineering

One-pot synthesis of aminoindolizines and chalcones using

CuI/CSP

nanocomposites

with

anomalous

selectivity under green conditions U. Chinna Rajesh, Gunjan Purohit and Diwan S. Rawat* Department of Chemistry, University of Delhi, Delhi-110007, India Fax: 91-11-27667501; Tel: 91-11-27662683; *E-mail: [email protected]

KEYWORDS: aminoindolizines, A3 coupling reaction, chalcones, green chemistry, E-factor and atom economy.

ABSTRACT: CuI/CSP nanocomposites were found to be efficient, and recyclable nanocatalysts for onepot synthesis of aminoindolizines via A3 coupling reaction in the presence of ethylene glycol (EG) as a recyclable solvent. In contrast, chalcones were isolated when the reaction was performed in the presence of secondary amines such as piperidine, 3-methylpiperidine, pyrrolidine and piperazine under solvent free conditions. The CuI/CSP was recycled for five times without significant loss in its catalytic activity. The anomalous selectivity in the formation of aminoindolizines and chalcones was dependent of solvents and secondary amines used for the reaction. The present methodology is facile and follows green principles with higher atom economy (94%), smaller E-factor (0.06).

1

ACS Paragon Plus Environment


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INTRODUCTION Carbon spheres (CSP) have been considered as sustainable catalyst supports for various metal NPs with specific catalytic properties and greatly widen their utility in the fields of nanocatalysis.1 The CSP could be prepared by various methods,2,3 and the hydrothermal carbonization from glucose as a carbon source without using any template is the simple and green method.4,5 During hydrothermal carbonization process, glucose was first polymerized as polysaccharide in water, and then formed small spheres with inner core of completely carbonized hydrophobic carbon layer and the outer surface with incompletely carbonized hydrophilic polysaccharide layer.6 Amphiphilic carbon spheres (CSP) are readily dispersible in various solvents of different polarity without any prior surface modifications.7 The outer polysaccharide surface of CSP has many functional groups such as hydroxyl, carboxylic, aldehyde groups, which are suitable for the stabilization of various metal NPs.8-11 Recently, Pd/CSP composites were found to be efficient amphiphilic catalysts for Heck, Ullmann, Suzuki–Miyaura and selective partial hydrogenation reactions in aqueous medium.12-14 Till date, copper/CSP composites have been reported for very limited applications such as surface-enhanced Raman scattering substrate,15 efficient anodes for lithium-ion batteries,16 or CSP as a template for synthesis of porous CuO hollow spheres.17,18 However, although CuI alone19 or Cu NPs stabilized on various supported materials20 have been found potential applications in the field of nanocatalysis, but CuI/CSP composites have not been investigated as catalysts for the multi-component organic synthesis. Multi-component reactions (MCR) promoted by recyclable nanocatalysts under green reaction conditions provide an efficient tool for the sustainable synthesis of heterocycles.21 Indolizines are unique N-fused heterocycles, have been found in pharmacological relevance molecules with a wide range of biological activities (Figure 1).22 2


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Me O

N

CN

HO

N

Et

CN O

Ph

N

N

O Ph O

PDE5A inhibitor

Antibacterial & antifungal

O N

N H

N

O O

Anticonvulsant & antiinflammatory

N

H N

N

N N

O

Anti-tubercular

O

Histamine H3 receptor antagonist

Figure 1: Biologically active indolizine scaffolds Among the various known methodologies for the synthesis of indolizines,23-27 one-pot three component reaction between pyridine-2-carboxaldehyes, secondary amines and phenylacetylenes via A3 coupling followed by cycloisomerization is one of the efficient approaches. Till date, very limited catalytic systems have been developed for the synthesis of aminoindolizines via A3 coupling strategy.28-34 Alonso et al. reported the use of CuO/Cu2O/activated charcoal (Cu NPs/C) as a heterogeneous catalyst for solvent-dependent synthesis of indolizines and chalcones.35 However, this method has advantages over the reported homogeneous catalysis such as usage of low catalyst loading, simple work up procedure etc. But it has a drawback of catalyst recyclability due to the leaching of Cu NPs from its carbon support and usage of toxic organic solvents. Still, there is a need of developing truly recyclable heterogeneous catalysts under green reaction conditions. With this background, and as a part of our ongoing research towards green chemistry and nanocatalysis,36-44 we herein report the facile one-pot synthesis of aminoindolizines using CuI/CSP nanocomposites with anomalous selectivity under green conditions.

3



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RESULTS AND DISCUSSION CuI/CSP nanocomposites were synthesized by refluxing the mixture of CuI and carbon spheres (CSP) in ethanol as shown in Figure 2. The CSP were prepared by hydrothermal carbonization of glucose at 180 o

C by following the literature procedure.1 Next, the CuI was stabilized on polysaccharide surface of CSP

by mixing of CuI and CSP in equal ratio in ethanol at conventional reflux condition (Figure 2).

OH

H

H O O O H

OH

CuI H

CuI

O OH H

H OH

H

H OH

H

OH

(i) Hydrothermal treatment, 180 oC, 6h

H

HO

H

CuI

OH

H

H H HO

H

H

O H

H

H O

O H HO

H

CuI

H OH

O

O

H

Glucose

CuI

CuI

HO OH

H

OH OH

O

H

O

H

H

O H

H OH

CuI

O

CuI

(ii) CuI Ethanol, reflux, 2h

H H O

HO

OH

H

H O HO HO

H

O

H

H O

HO

O H

CuI/CSP

HO H

Figure 2: Schematic representation for the preparation of CuI/CSP nanocomposites The CuI/CSP nanocomposites were characterized by using various techniques such as powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), scanning electronic microscopy (SEM), transmission electronic microscopy (TEM), thermal gravimetric analysis (TGA), X-ray photoelectron spectra (XPS), Inductively coupled plasma atomic emission spectroscopy (ICP-AES) etc. The powder XRD of CuI/CSP composites revealed the existence of crystalline CuI with phases (111), (200), (220), (311), (222), (400), (331) and (420) of corresponding diffraction peaks at 2θ are 25.36, 29.36, 42.16, 49.89, 52.29, 61.08, 67.48, 69.48 respectively (JCPDS, 06-0246), as shown in Figure 3.

4


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The average crystalline size of CuI NPs was calculated by using Scherrer equation and found to be 13 nm.

Intensity (a.u.)

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20

30

40

50

60

70

Two theta (degree)

Figure 3: PXRD of CuI/CSP composites

The functional groups of CSP and CuI/CSP composites were characterized by using FT-IR spectra as shown in Figure 4.6 The broad band at 3405 cm-1 corresponds to the hydroxyl functionalities on the surface of CSP. The presence of carbonyl (C=O) and unsaturated (C=C) groups were conformed from the bands at 1701 cm-1 and 1614 cm-1 respectively, and these groups support the concept of aromatization of glucose during hydrothermal treatment. Moreover, the presence of –C–OH (1190 cm-1), and glycosidic –C–O–C– linkages (1099 cm-1) were also conformed from FT-IR technique as shown in Figure 4. The existences of these functional groups on carbon framework of CSP improve the stability of CuI NPs on its surface.

5


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% Transmittance


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(b) CuI/CSP

3405

(a) CSP

1190 1701 1457 1614

1099 742

4000

3500

3000

2500

2000

1500

1000

500

-1 Wavenumber (cm )

Figure 4: FT-IR of (a) CSP; and (b) CuI/CSP nanocomposites

The surface and internal morphologies of CuI/CSP nanocomposites were characterized from SEM and TEM respectively (Figure 5). Figure 5a shows the surface morphology of CSP as spheres with various sizes, and the SEM image of CuI/CSP show the existence of spheres, distorted spheres, and cubes of various size ranges from 2 to 8 µm (Figure 5b). It is also showing the existence of CuI NPs on the surface and in between the various carbon spheres. The internal morphology of CuI/CSP reveals that the assembling of porous rods in the spherical shape and the length of these rods varies from 100 to 320 nm (Figure 5c). The porous and crystalline nature of carbon and CuI NPs (inset of Fig. 5d) were conformed from TEM and SAED respectively (Figure 5d).

6


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Figure 5: SEM images of (a) CSP (b) CuI/CSP; and TEM images (c), (d) of CuI/CSP (inset of d, is SAED of CuI) The oxidation state of copper in CuI/CSP composites was determined from X-ray photoelectron spectra (XPS) as shown in Figure 6. The presence of Cu(+1) was conformed from the binding energies at 932 ev and 620 ev corresponds to Cu(+I)2p and I (-1)3d respectively.45 The binding energy peak at 284 ev corresponds to carbon content (C1S) of CSP and (see SI).46

60000

50000

I3d

2pCu 40000

CPS

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


C1s 30000

20000

10000

0 1000

800

600

400

200

0

Binding Energy (eV)

Figure 6: X-ray photoelectron spectrum (XPS) of CuI/CSP nanocomposites 7



The thermal decomposition of CuI/CSP composites was studied by TGA and DTG analysis in the temperature range 100 to 800 oC at the rate of 10 oC per minute under nitrogen atmosphere as shown in Figure 7. The weight loss at temperature range 200-270 oC is about 13.59% due to the loss of surface hydroxyls and water molecules in the CSP of composite nanoparticles. In the second step the maximum weight loss is about 30.7% at the temperature range 350-360 oC is due to the combustion of amorphous carbon. The final weight loss of 48.4% at the temperature range from 390-560 oC is may be a response to decomposition of CuI and some residual carbon (Figure 7).

(a) TGA (b) DTG

(a)

100

80

80

60

60

40

40 (b)

20

20

0

o Deriv. weight (%/ C)

100

Mass (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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0 0

100

200

300

400

500

600

700

800

o Temperature ( C)

Figure 7: TGA and DTG analysis of CuI/CSP composites The EDAX elemental analysis of CuI/CSP composites reveals the presence of Cu in 14.4 At% and iodide was found to be 11.7 At% as shown in Figure 8. The sum of copper (Cu+1) and iodide (I-) was calculated as 26.1 At% and the remaining approx. 74.0 At% may belongs to carbon and polysaccharide functional groups (carbon 68.16 At% and oxygen 5.74 At%). The average weight percentage of copper in CuI/CSP was found to be 19.10 Wt%. The weight percentage of copper in CuI/CSP composites was

8


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calculated from ICP-AES analysis and found to be 19.70 wt%, which is almost inconsistent with EDAX analysis.

Figure 8: EDAX elemental analysis of CuI/CSP composites

CuI/CSP composites as nanocatalysts for synthesis of aminoindolizine: Initially, the model reaction was performed among pyridine-2-carboxaldehyde (1a), morpholine (2a), and phenylacetylene (3a) using 5 mg of CuI/CSP catalyst in the presence various solvents at different temperatures as shown in Table 1. Table 1: Optimization study for CuI/CSP catalyzed synthesis of aminoindolizine (4aa).a O

N CHO N

O Catalyst +

+

Ph N

N 1

2a

Solve nt, Temp. Ph

3a

4aa

9



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a

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Entry

Catalyst

Solvent

Temp. ( oC)

Time (h)

Yield of 4aa (%)b

1

CuI/CSP

Toluene

100

3

83

2

CuI/CSP

DMSO

100

3

86

3

CuI/CSP

DMF

100

3

82

4

CuI/CSP

Water

100

3

90

5

CuI/CSP

Glycerin

100

2

88

6

CuI/CSP

EG

100

0.5

94

7

CuI/CSP

EG

80

0.5

94

8

CuI/CSP

EG

60

0.5

94

9

CuI/CSP

neat

60

1

90

10

CuI/CSP

EG/neat

rt

10

trace

EG

60

10

60

b

11

CuI (bulk)

12

CuI (bulk) + CSP

EG

60

6

75

13

CSP

EG

60

24

No product

14

No catalyst

EG

60

24

No product

Reaction conditions: Pyridine-2-carboxaldehye 1 (1 mmol), morpholine 2a (1 mmol), phenylacetylene 3 (1 mmol),

CuI/CSP catalyst (5 mg), solvent (3 mL) were stirred at appropriate temperature.

To our delight, the desired aminoindolizine (4aa) was obtained selectively in excellent yield in the presence of either all solvents such as toluene, DMSO, DMF, water, glycerin, EG or neat condition at temperature 60 to 100 oC (Table1, Entries 1-9). However, the reactions were sluggish at room temperature in the presence of either EG or neat condition (Entry 10). The model reaction was performed either in presence of bulk CuI alone or physical mixture of bulk CuI and CSP to afford the product in moderate to good yields in longer reaction time 6-10 h (Entries 11, 12). But when the reaction was performed using either CSP alone as catalyst or without any catalyst, the product formation was not observed even after 24 h (Entries 13, 14). The results reveal that EG and neat conditions at 60 oC were the best to afford the product (4aa) in excellent yield in short reaction time (Table 1, Entries 6-9).

10


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The generality of present method was studied with the wide range of substrates including pyridine-2carboxaldehye, various alkynes including phenylacetylenes (3a-3d) and ethyl propiolate (3e) and secondary amines such as morpholine, thiomorpholine, phenylpiperazine, 1-(o-tolyl)piperazine, 3metylpiperidine, piperidine and N-methylaniline as shown in Scheme 1.

1

R

N

R

2

CHO R1 N

R2

+

N H

+

CuI/CSP catal. (3 mg)

R

N

o

E G or neat, 60 C

1

2

3

R

4

R = C6H5 ( 3a); 4-OMeC6 H4 ( 3b); 4-MeC6 H4 ( 3c); 4-FC6H4 (3d); CO2 Et ( 3e ) Ph O

S

Me

N N

Me

NH HN

N H

N H

N H

2a

2b

2c

Me

2d

N H

N H

2e

2f

Ph

2g

Scheme 1: CuI/CSP catalyzed one-pot synthesis of aminoindolizine derivatives

To our delight almost all screened substrates underwent smooth cycloisomerization to afford the aminoindolizines exclusively in 75% to 95% yields in EG solvent as shown in Table 2. However, it is interesting to see that the product formation was dependent of secondary amines under solvent free conditions. Aminoindolizines were obtained as major products in the presence of secondary amines such as morpholine (2a), thiomorpholine (2b), phenylpiperazine (2c), 1-(o-tolyl)piperazine (2d), and Nmethylaniline (2g) (Table 2). Heterocyclic chalcones (5a-5c) were obtained as major products in the presence of 3-metylpiperidine (2e), piperidine (2f), pyrrolidine (2h) and piperazine (2i) as shown in Table 4. 11



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Table 2: CuI/CSP catalyzed synthesis of aminoindolizine derivatives in EG and solvent free condition. O

O

O

N

N

N

N

N

N

N

N

N

N O

EtO

4ae

4ab

4aa

EG; Yield, 92% Neat; Yield, 90%

S

O

OMe

4ac


S

4bc

Me


S


Me

EG; Yield, 89% Neat; Yield, 83% Ph

Ph

Ph

N

N

N

N

N

N

N

N

N

N

N

N

N

O

EtO

O

EtO

4be

4bd

4ca

F

4cb

4ce O Me


N


Me

N

Me

N

N

N

N



Me

N

N

N


N

Me

N

N

N

N

N

O EtO

4da

4db

4dc O Me


Me


4de

4dd


F


12



Me

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Me

Me

Me N

Ph

Ph

N

Me

N

N N

N

N

N

N N

4ga

4gc

Me

4ea 4ed


4fa

F





With these interesting results in our hand, we further investigated the effect of solvents on the selectivity of chalcone and aminoindolizine formation in the presence of piperidine as shown in Table 3. Heterocyclic chalcone 5a was obtained in 75% and 90% conversions with exclusive E-stereochemistry in the presence of water and neat conditions respectively (Table 3, Entry 1 and 5). Aminoindolizine (4fa) was observed in 90% and 85% conversions in the presence of EG and PEG respectively (Entry 2 and 3). However, the conversions of chalcone (5a) and aminoindolizine (4fa) were observed in the equal ratio (50:50%) in the presence of glycerin (Entry 4). When the reaction was performed in the absence of catalyst, the reaction was sluggish (Table 3, Entry 6).

Table 3: Effect of solvents on the selectivity of chalcone (5a) and aminoindolizine (4fa).a

O

N

Piperidine

CHO

Ph N

1

+

Ph

CuI/CSP catal. (3 mg) 3a

o

Solvent, 60 C

N

5a

13


+

N

4fa

Ph


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Entry

a

Solvent

Page 14 of 27

Conversions (%)b

Time (min) 5a

4fa

1

Water

180

75

15

2

EG

30

trace

90

3

PEG

60

trace

85

4

Glycerin

120

50

50

5

Neat

45

90

10

6

Neatc

120

-

-

Reaction conditions: Pyridine-2-carboxaldehye 1 (1 mmol), piperidine 2d (1 mmol), phenylacetylene 3a (1 mmol), CuI/CSP

catalyst (5 mg) were stirred under neat conditions at 60 oC. bConversions are calculated from 1HNMR of reaction mixtures. c

Reaction was performed without catalyst.

Furthermore, we studied the effect of remaining secondary amines such as 3-metylpiperidine (2e), pyrrolidine (2h) and piperazine (2i) on the selectivity of product formation under solvent free condition as shown in Scheme 2 and Table 4. To our delight, all these secondary amines (2e, 2f, 2h, 2i) afforded chalcones 5a, 5b, and 5c in good to excellent yields 75-93% (Table 4).

O CHO R N

+

1

R N H

1

2

Ar

2

N

2e

Neat, 60 oC

3a H N

Me

N H

Ar

CuI/CS catal. (3 mg) +

5a-5c

Ar

=

C6H 5 (3a)

N H

N H

N H

= OMeC6H4 (3b)

2f

2h

2i

= MeC6H 4 (3c)

Scheme 2: Synthesis of E-selective heterocyclic chalcones.

14


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Table 4: CuI/CSP catalyzed synthesis of chalcones under solvent free condition.

a

Entry

Amines (2)

Ar (3)

Chalcones (5)

Yield of 5 (%)

1

2e

C6H5

5a

78

2

2e

OMeC6H4

5b

75

3

2f

C6H5

5a

90

4

2f

OMeC6H4

5b

85

7

2f

MeC6H4

5c

87

8

2h

C6H5

5a

97

9

2i

C6H5

5a

79

10

2i

OMeC6H4

5b

75

Reaction conditions: Pyridine-2-carboxaldehye 1 (1 mmol), amines 2d/2e/2f (1 mmol), phenylacetylenes 3 (1 mmol),

CuI/CSP catalyst (5 mg) were stirred under neat conditions at 60 oC.

Next, the green and sustainability factors such as atom economy and E-factor of present method were calculated for the model reaction between pyridine-2-carboxaldehyde (1a), morpholine (2a), and phenylacetylene (3a) to afford the aminoindolizine (4aa). The results indicate that the present method follows green chemistry principles with smaller E-factor as 0.06 and high atom economy (AE) as 94% (see ESI for calculations). Moreover, the comparative study of CuI/CSP catalyst with the reported methods clearly indicates the superiority of present method in terms of selectivity, recyclability, green and mild reaction conditions as shown in Table 5.

15



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Table 5: Comparative study of various catalysts for the synthesis of aminoindolizine (4aa)

a

S. No

catalyst

solvent

Yield of [Ref] 4aa (%)

Recycle of catalyst

1

ZnI2

Toluene

90

[29]

No

2

Cu NPs/C

DCM

74

[30], [28]

No

3

CuCl

PEG

96

[31]

No

4

CuIa

Toluene

96

[32]

No

5

Fe(acac)3

TBAOH DMSO

83

[33]

No

6

AgBF4

Toluene

89

[34]

No

7

NaAuCl4.2H2O

neat

95

[35]

No

8

CuI/CSP

EG

92

Present

yes

CuI reported as homogeneous catalyst for coupling reaction among methyl N-allyl-1-formyl-9H-β-carboline-3-carboxylate,

morpholine, and phenyl acetylene.

The plausible mechanism for the formation of aminoindolizine via A3 coupling followed by cycloisomerization is well known in the literature.28-34 Very recently, Alonso et al. reported synthetic and mechanistic studies on the solvent-dependent Cu NPs/C catalyzed formation of aminoindolizine and chalcones.35 They have demonstrated the formation of propargyl amines (A3 product) as intermediate for aminoindolizine using GC-MS analysis. The X-ray structure of chalcone and reaction mechanism for the formation of chalcone was determined from isotopic-labeling experiments.35 In order to understand the detailed mechanism, we would be pursuing the theoretical studies for CuI/CSP catalyzed formation of aminoindolizine and chalcones with dependent of secondary amines and solvents. We performed recyclability experiments to study the advantage of the CuI/CSP nanocomposite catalyst over the physical mixture of CuI (bulk) and CSP. The recyclability of CuI/CSP catalyst was studied for a model reaction to afford aminoindolizine (4aa) in the presence of EG under optimized reaction condition as shown in Figure 9. After completion of reaction, water was added to the reaction 16


Page 17 of 27

mixture to recover EG from aqueous layer. Next, ethanol was added to the reaction mixture to separate the solid CuI/CSP NPs from organic layer by centrifuge. The catalyst was washed several times with ethanol and dried at 90 oC in oven for 10 h. The recovered CuI/CSP catalyst and EG solvent were reused in model reaction to afford the product in 90% yield, and the procedure was repeated for four more times and found that there was no significant loss in its catalytic activity (Figure 9). But the reutilization of physical mixture was inefficient due to leaching of CuI or catalyst poisoning.28

100 90 80 70

Yield of 4aa (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


60 50 40 30 20 10 0 1

2

3

4

5

No. of Cycles

Figure 9: Recyclable study of CuI/CSP catalyst for synthesis of (4aa) Furthermore, we studied the heterogeneity of model reaction for the synthesis of 4aa in water as a solvent at 90 oC by hot filtration test experiment. The reaction was stopped at 50% conversion of starting materials that is in 30 min and filtered out the catalyst from reaction mixture. The filtrate was further continued for stirring at 90 oC for 10h, the reaction did not proceed indicating that no catalytically active Cu remained in the filtrate. The filtrate was analyzed from ICP-AES to study the presence of copper at ppm level, but we did not observe any Cu content in it. The hot filtration test and ICP-AES analysis results revealed that there was no leaching of CuI NPs from CSP support. 17



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CONCLUSION

In summary, we have developed a facile and green protocol for one-pot synthesis of aminoindolizines and chalcones from the same reactants with anomalous selectivity dependent of secondary amines and solvents. Ethylene glycol was the best recyclable solvent to afford the aminoindolizines exclusively from wide range of substrates. However, the selectivity in the product formation depends on the secondary amines used in the reaction under solvent free conditions. Heterocyclic chalcones with Estereochemistry were obtained in excellent yield in the presence of 3-methylpiperidine, piperidine, pyrrolidine and piperazine. The present protocol follows green and sustainable principles with higher atom economy (94%), and smaller E-factor (0.06). Moreover, the CuI/CSP catalyst was recycled for five times without significant loss in its catalytic activity.

EXPERIMENTAL SECTION

Typical procedure for synthesis of CuI/CSP composites: Glucose (6 g) was dissolved in distilled water (60 mL) and the resulted clear solution was added to 600 mg of Ph3P in teflon container of 100 mL capacity in stainless steel autoclave. The reaction was maintained at 180 °C for 6 h, and then cooled to room temperature. The dark precipitate of carbon spheres were collected by centrifuge and washed several times with ethanol. The carbon spheres were dried in a vacuum oven at 80 °C for 6 h. The freshly prepared carbon spheres (200 mg) and CuI (200 mg) were mixed in a 100 mL round bottom flask containing 40 mL of ethanol. The reaction mixture was sonicated for 60 min and followed by refluxed at 90 oC for 2 h. The resulting CuI/carbon sphere (CuI/CSP) composites were collected by centrifugation and were dried at 80 °C under vacuum. 18


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General Procedure for synthesis of aminoindolizines (4) and chalcones (5): A mixture of pyridine-2carboxaldehye 1 (1 mmol), secondary amines 2 (1 mmol), phenylacetylenes 3 (1 mmol) and CuI/CSP catalyst (5 mg), were stirred at 60 oC in ethylene glycol (2 mL) or solvent free condition until the reaction was completed as monitored by TLC. After completion of the reaction, ethanol was added to the mixture and the catalyst was separated from organic layer by centrifugation. The recovered catalyst was washed with ethanol for 3-4 times to remove all adsorbed organic substrates from its surface and dried at 80 oC in vaccume oven to reuse it in further cycles. The organic layer was evaporated and the crude products were purified by flash chromatography.

ASSOCIATED CONTENT Electronic Supplementary Information (ESI) available [Characterization of recycled CuI/CSP composites such as PXRD, SEM, TEM, and XPS of recycled catalyst, Green metric calculations; 1

HNMR, 19F NMR and 13C NMR spectral data and spectra of all compounds)

ACKNOWLEDGMENT

DSR thanks DU-DST PURSE grant and University of Delhi, Delhi, India for financial support. UCR thanks University Grants Commission (UGC) for the award of a senior research fellowship (SRF). We thank USIC-CIF, University of Delhi, for assisting to acquire analytical data.

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REFERENCES 1. Sun, X.; Li, Y. Colloidal carbon spheres and their core/shell structures with noble-metal nanoparticles, Angew. Chem. Int. Ed. 2004, 43, 597–601. 2. Nieto-Marquez, A.; Romero, R.; Romero, A.; Valverde, J. L. Carbon nanospheres: Synthesis, physicochemical properties and applications, J. Mater. Chem. 2011, 21, 1664– 1672. 3. Deshmukh, A. A.; Mhlanga, S. D.; Coville, N. J. Carbon spheres, Mater. Sci. Eng. 2010, 70, 1–28. 4. Sun, X.; Li, Y. Hollow carbonaceous capsules from glucose solution, J. Colloid Interface Sci. 2005, 291, 7–12. 5. Li, M.; Wu, Q.; Wen, M. A novel route for preparation of hollow carbon nanospheres without introducing template, Nanoscale Res. Lett. 2009, 4, 1365–1370. 6. Li, M.; Li, W.; Liu, S. Hydrothermal synthesis, characterization and KOH activation of carbon spheres from glucose, Carbohydr. Res. 2011, 346, 999–1004. 7. Titirici, M. M.; Antonietti, M. Chemistry and materials options of sustainable carbon materials made by hydrothermal carbonization, Chem. Soc. Rev. 2010, 39, 103–116. 8. Tang, S.; Vongehr, S.; Meng, X. Carbon spheres with controllable silver nanoparticle doping, J. Phys. Chem. C, 2010, 114, 977–982.

20


Page 21 of 27

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


9. Tang, S.; Vongehr, S.; Meng, X. Controllable incorporation of Ag and Ag–Au nanoparticles in carbon spheres for tunable optical and catalytic properties, J. Mater. Chem. 2010, 20, 5436–5445. 10. Yang, Q.; Zhang, J.; Zhang, L.; Fu, H.; Zheng, X.; Yuan, M.; Chen, H.; Li, R. Ruthenium nanoparticles on colloidal carbon spheres: An efficient catalyst for hydrogenation of ethyl lactate in aqueous phase, Catal. Commun. 2013, 40, 37–41. 11. Xu, C.; Cheng, L.; Shen, P.; Liu, Y. Methanol and ethanol electro-oxidation on Pt and Pd supported on carbon microspheres in alkaline media, Electrochem. Commun. 2007, 9, 997– 1001. 12. Kamal, A.; Srinivasulu, V.; Seshadri, B. N.; Markandeya, N.; Alarifib, A.; Shankaraiah, N. Water mediated Heck and Ullmann couplings by supported palladium nanoparticles: Importance of surface polarity of the carbon spheres, Green Chem. 2012, 14, 2513-2522. 13. Putta, C. B.; Ghosh, S. Palladium nanoparticles on amphiphilic carbon spheres: A green catalyst for Suzuki–Miyaura reaction, Adv. Synth. Catal. 2011, 353, 1889–1896. 14. Makowski, P.; Cakan, R. D.; Antonietti, M.; Goettmann, F.; Titirici, M. M. Selective partial hydrogenation of hydroxy aromatic derivatives with palladium nanoparticles supported on hydrophilic carbon, Chem. Commun. 2008, 999–1001. 15. Qian, Y.; Lu, S.; Gao, F. Synthesis of copper nanoparticles/carbon spheres and application as a surface-enhanced Raman scattering substrate, Mater. Letter. 2012, 81, 219–221.

21



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 27

16. Xu, Y.; Jian, G.; Zachariah, M. R.; Wang, C. Nano-structured carbon-coated CuO hollow spheres as stable and high rate anodes for lithium-ion batteries, J. Mater. Chem. A, 2013, 1, 15486–15490. 17. Jia, B.; Qin, M.; Zhang, Z.; Chu, A.; Zhang, L.; Liu, Y.; Lu, H.; Qu, X. One-pot synthesis of Cu–carbon hybrid hollow spheres, Carbon, 2013, 62, 472-480. 18. Cheng, Y.; Niu, X.; Zhao, T.; Yuan, F.; Zhu, Y.; Fu, H. Hydrothermal synthesis of Cu@C composite spheres by one-step method and their use as sacrificial templates to synthesize a CuO@SiO2 core–shell structure, Eur. J. Inorg. Chem. 2013, 4988–4997. 19. Allen, S. E.; Walvoord, R. R.; Salinas, R. P.; Kozlowski, M. C. Aerobic copper-catalyzed organic reactions, Chem. Rev. 2013, 113, 6234−6458. 20. Decan, M. R.; Impellizzeri, S.; Marin, M. L.; Scaiano, J. C. Copper nanoparticle heterogeneous catalytic 'click' cycloaddition confirmed by single-molecule spectroscopy, Nature Commun. 2014, 5: 4612 DOI: 10.1038/ncomms5612. 21. Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Small heterocycles in multicomponent reactions, Chem. Rev. 2014, 114, 8323−8359; 22. Sharma, V.; Kumar, V. Indolizine: A biologically active moiety, Med. Chem. Res. 2014, 23, 3593–3606. 23. Liu, Ren-R.; Cai, Zheng-Y.; Lu, Chuan-J.; Ye, Shi-C.; Xiang, B.; Gao, J.; Jia, Yi-X. Indolizine

synthesis

via

Cu-catalyzed

cyclization

nucleophiles, Org. Chem. Front. 2015, 2, 226–230. 22


of

2-(2-enynyl)pyridines

with

Page 23 of 27

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


24. Xiang, L.; Yang, Y.; Zhou, X.; Liu, X.; Li, X.; Kang, X.; Yan, R.; Huang, G. I2‑Mediated oxidative cyclization for synthesis of substituted indolizines, J. Org. Chem. 2014, 79, 10641−10647. 25. Kucukdisli, M.; Opatz, T. One-pot synthesis of polysubstituted indolizines by an addition/cycloaromatization sequence, J. Org. Chem. 2013, 78, 6670−6676. 26. Yang, Y.; Xie, C.; Xie, Y.; Zhang, Y. Synthesis of functionalized indolizines via coppercatalyzed annulation of 2-alkylazaarenes with α,β-unsaturated carboxylic acids, Org. Lett. 2012, 14, 957–959. 27. Barluenga, J.; Lonzi, G.; Riesgo, L.; Lopez, L. A.; Toma´s, M. Pyridine activation via copper(I)-catalyzed annulation toward indolizines, J. Am. Chem. Soc. 2010, 132, 13200– 13202. 28. Albaladejo, M. J.; Alonso, F.; González-Soria, M. J. Synthetic and mechanistic studies on the solvent-dependent copper-catalyzed formation of indolizines and chalcones, ACS Catal. 2015, 5, 3446−3456. 29. Mishra, S.; Bagdi, A. K.; Ghosh, M.; Sinha, S.; Hajra, A. Zinc iodide: A mild and efficient catalyst

for

one-pot

synthesis

of

aminoindolizines

via

sequential

A3

coupling/cycloisomerization, RSC Adv. 2014, 4, 6672–6676. 30. Albaladejo, M. J.; Alonso, F.; Yus, M. Synthesis of indolizines and heterocyclic chalcones catalyzed by supported copper nanoparticles, Chem. Eur. J. 2013, 19, 5242 –5245.

23



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 27

31. Mishra, S.; Naskar, B.; Ghosh, R. CuCl catalyzed green and efficient one-pot synthesis of aminoindolizine frameworks via three-component reactions of aldehydes, secondary amines, and terminal alkynes in PEG, Tetrahedron Lett. 2012, 53, 5483–5487. 32. Dighe,

S.

U.;

Hutait,

coupling/cycloisomerization

S.; reaction

Batra,

S.

between

Copper-catalyzed substituted

multi-component

1-formyl-9H-β-carbolines,

secondary amines, and substituted alkynes for the synthesis of substituted 3aminoindolizino[8,7-b]indoles, ACS Comb. Sci. 2012, 14, 665−672. 33. Patil, S.; Patil, S. V.; Bobade, V. D.; Synthesis of aminoindolizine and quinoline derivatives via Fe(acac)3/TBAOH-catalyzed sequential cross-coupling–cycloisomerization reactions, Synlett, 2011, 2379-2383. 34. Bai, Y.; Zeng, J.; Ma, J.; Gorityala, B. K.; Liu, Xue-W. Quick access to druglike heterocycles: Facile silver-catalyzed one-pot multicomponent synthesis of aminoindolizines, J. Comb. Chem. 2010, 12, 696–699. 35. Yan, B.; Liu, Y. Gold-catalyzed multicomponent synthesis of aminoindolizines from aldehydes, amines, and alkynes under solvent-free conditions or in water, Org. Lett. 2007, 9, 4323-4326. 36. Rajesh, U. C.; Pavan, V. S.; Rawat, D. S. Hydromagnesite rectangular thin sheets as efficient heterogeneous catalysts for the synthesis of 3-substituted indoles via Yonemitsutype condensation in water, ACS Sustainable Chem. Eng. 2015, 3, 1536−1543.

24


Page 25 of 27

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


37. Rajesh, U. C.; Wang, J.; Prescott, S.; Tsuzuki, T.; Rawat, D. S. RGO/ZnO nanocomposite: An efficient, sustainable, heterogeneous, amphiphilic catalyst for synthesis of 3-substituted indoles in water, ACS Sustainable Chem. Eng. 2015, 3, 9-18. 38. Rajesh, U. C.; Kholiya, R.; Thakur, A.; Rawat, D. S. [TBA][Gly] Ionic liquid promoted multi-component synthesis of 3-substituted indoles and indolyl-4H-chromenes, Tetrahedron Lett. 2015, 56, 1790–1793. 39. Rajesh, U. C.; Divya, Rawat, D. S. Functionalized superparamagnetic Fe3O4 as an efficient quasi-homogeneous catalyst for multicomponent reactions, RSC Advances, 2014, 4, 41323– 41330. 40. Rajesh, U. C.; Kholiya, R.; Pavan, V. S.; Rawat, D. S. Catalyst-free, ethylene glycol promoted one-pot three component synthesis of 3-amino alkylated indoles via Mannich-type reaction, Tetrahedron Lett. 2014, 55, 2977-2981. 41. Rajesh, U. C.; Manohar, S.; Rawat, D. S. Hydromagnesite as an efficient recyclable heterogeneous solid base catalyst for the synthesis of flavanones, flavonols and 1,4dihydropyridines in water, Adv. Synth. Catal. 2013, 355, 3170–3178. 42. Thakur, A.; Tripathi, M.; Rajesh, U. C.; Rawat, D. S. Ethylenediammonium diformate (EDDF) in PEG600: an efficient ambiphilic novel catalytic system for the one-pot synthesis of 4H-pyrans via Knoevenagel condensation, RSC Adv. 2013, 3, 18142-18148.

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Page 26 of 27

43. Arya, K.; Rajesh, U. C.; Rawat, D. S. Proline confined FAU zeolite: Heterogeneous hybrid catalyst for the synthesis of spiroheterocycles via a Mannich type reaction, Green Chem. 2012, 14, 3344-3351. 44. Arya, K.; Rawat, D. S.; Sasai, H. Zeolite supported Bronsted-acid ionic liquids: An eco approach for synthesis of spiro[indole-pyrido[3,2-e]thiazine] in water under ultrasonication, Green Chem. 2012, 14, 1956–1963. 45. M. Yang, J. Xu, S. Xu, J. Zhu, H. Chen, Preparation of porous spherical CuI nanoparticles, Inorg. Chem. Commun. 2004, 7, 628–630. 46. Y. Z. Jin, C. Gao, W. K. Hsu, Y. Zhu, A. Huczko, M. Bystrzejewski, M. Roe, C. Y. Lee, S. Acquah, H. Kroto, D. R. M. Walton, Large-scale synthesis and characterization of carbon spheres prepared by direct pyrolysis of hydrocarbons, Carbon, 2005, 43, 1944–1953.

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TABLE OF CONTENTS (TOC) GRAPHIC

One-pot synthesis of aminoindolizines and chalcones using CuI/CSP nanocomposites with anomalous selectivity under green conditions U. Chinna Rajesh, Gunjan Purohit and Diwan S. Rawat* Department of Chemistry, University of Delhi, Delhi-110007, India Fax: 91-11-27667501; Tel: 91-11-27662683,*E-mail: [email protected]

CuI/CSP was found to be efficient, and recyclable nanocatalyst for one-pot synthesis of aminoindolizines and chalcones with anomalous selectivity under green conditions.


CSP

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